rs79074685

Positions:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_000492.4(CFTR):c.1365G>A(p.Ala455=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,555,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CFTR
NM_000492.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: -1.15

Variant links:

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR links:

CFTR-AS1 (HGNC:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 7-117548796-G-A is Benign according to our data. Variant chr7-117548796-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 35820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.15 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1365G>A	p.Ala455=	synonymous_variant	10/27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.222-6257C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1365G>A	p.Ala455=	synonymous_variant	10/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

209

AN:

128398

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00558

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000809

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000259

Gnomad FIN

AF:

0.00121

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000677

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000465

AC:

107

AN:

229864

Hom.:

AF XY:

0.000345

AC XY:

AN XY:

124496

show subpopulations

Gnomad AFR exome

AF:

0.00480

Gnomad AMR exome

AF:

0.000154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00137

Gnomad NFE exome

AF:

0.0000295

Gnomad OTH exome

AF:

0.000356

GnomAD4 exome

AF:

0.000185

AC:

264

AN:

1427304

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

112

AN XY:

709802

show subpopulations

Gnomad4 AFR exome

AF:

0.00416

Gnomad4 AMR exome

AF:

0.000139

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000267

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00123

Gnomad4 NFE exome

AF:

0.0000376

Gnomad4 OTH exome

AF:

0.000292

GnomAD4 genome

AF:

0.00164

AC:

211

AN:

128474

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

104

AN XY:

62492

show subpopulations

Gnomad4 AFR

AF:

0.00562

Gnomad4 AMR

AF:

0.0000808

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000260

Gnomad4 FIN

AF:

0.00121

Gnomad4 NFE

AF:

0.0000677

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000184

Hom.:

Bravo

AF:

0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Oct 11, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 25, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

Cystic fibrosis

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 19, 2014	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 14, 2023	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 18, 2022	Variant summary: CFTR c.1365G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00047 in 229864 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00047 vs 0.013), allowing no conclusion about variant significance. c.1365G>A has been reported in one individual with chronic respiratory problems without evidence of causality (Shrijver_2005). This report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, though 4 classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

CFTR-related disorder

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 05, 2019	- -

Hereditary pancreatitis

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Nov 09, 2020

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.1

DANN

Benign

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over